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Single-Cell Atlas of Human Lung Identifies New, Known Cell Types

NEW YORK – Researchers have generated a cellular atlas of the human lung that highlights the more than four dozen cell types residing there using single-cell RNA sequencing. 

By developing an atlas of lung cells, researchers led by Stanford University School of Medicine's Mark Krasnow aimed to systematically identify what cells are present and examine their functions.

He and his colleagues generated high-quality transcriptomes from about 75,000 cells from different parts of the human lungs. As they reported in the journal Nature on Wednesday, these cells clustered into 58 transcriptionally distinct groups, including groups representing previously unknown cell types. With this atlas, they could begin to tease out the functions and cellular interactions of the cell types as well as compare the complement of human lung cells to those of mice to study lung evolution. 

"This atlas provides the molecular foundation for investigating how lung cell identities, functions, and interactions are achieved in development and tissue engineering and altered in disease and evolution," Krasnow and his colleagues wrote in their paper.

To develop the atlas, they collected normal tissue from the bronchi, bronchiole, and alveolar regions of the lung along with peripheral blood samples. After dissociating the lung samples into cell suspensions, the researchers sorted the cells into epithelial, endothelial or immune, and stromal populations. They prepared the sequencing libraries using either the 10x Genomics Chromium platform or the Illumina SmartSeq2 platform, as the higher throughput of the 10x platform allowed the detection of rare cell types, while the SmartSeq2 platform provided deeper transcriptomic data. In all, the researchers generated high-quality transcriptomes for about 75,000 cells.

Based on their expression of lung compartment-specific markers, the researchers iteratively clustered the cells to uncover 58 transcriptionally distinct cell populations. They generated genome-wide expression profiles for 91 percent of classical lung cell types — missing cell types that are extremely rare or need to be specially isolated — and 14 previously unknown lung cell types.

Some of the canonical cell types were represented by multiple clusters, suggesting the clusters may represent particular molecular states, novel cell types, or subtypes. For instance, they uncovered two clusters of alveolar type 2 cells, which produce surfactants. One cluster expressed higher levels of the canonical AT2 markers, but also some Wnt and Hedgehog inhibitors, indicating the cells are quiescent. The other cluster, meanwhile, expressed Wnt signaling genes and detoxification genes.

The researchers additionally uncovered 200 markers could differentiate between the known and newly identified lung cell types.

The lung cell atlas also enabled the researchers to trace the targets of circulating hormones. Some hormone receptors, they noted, are broadly expressed throughout the lungs, but others are more specific. They found, for instance, that somatostatin targets the arteries, while melanocortin targets ionocytes and oxytocin ciliated cells.

Similarly, the researchers examined where 233 genes associated with lung disease are expressed. This implicated pericytes in pulmonary hypertension, capillaries in atrioventricular dysplasia, and ATS cells in chronic obstructive pulmonary disease. Additionally, by examining where genes encoding viral receptors are expressed, they connected club, ciliated, differentiating basal, and goblet cells to the measles, ciliated and neuroendocrine cells in the common cold, and AT2 cells in coronavirus like SARS, SARS-CoV-2, and MERS.

When they compared the human lung cell atlas to one of mouse lungs, the researchers noted mice don't have about 30 percent of the 58 human lung cell types, while people only lack five mouse lung cell types. Based on this, they said there may have been substantial diversification of lung cell types during mammalian evolution, particularly along the human lineage.

"The atlas has broad implications for physiology and medicine, providing insight into the functions, regulation and interactions of the known and new cell types," the researchers added.